Phenotypic signatures of circulating neoantigen-reactive CD8+ T cells in patients with metastatic cancers

Author:

Yossef, Rami

Krishna, Sri

Sindiri, Sivasish

Lowery, Frank J

Copeland, Amy R

Gartner, Jared J

Parkhurst, Maria R

Parikh, Neilesh B

Hitscherich, Kyle J

Levi, Shoshana T

Chatani, Praveen D

Zacharakis, Nikolaos

Levin, Noam

Vale, Nolan R

Nah, Shirley K

Dinerman, Aaron

Hill, Victoria K

Ray, Satyajit

Bera, Alakesh

Levy, Lior

Jia, Li

Kelly,Michael

Goff, Stephanie L

Robbins, Paul F

Rosenberg, Steven A
Author Address

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: yosef.rami@gmail.com., Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: sri.krishna@nih.gov., National Institutes of Health Library, National Institutes of Health, Bethesda, MD 20892, USA., Single Cell Analysis Facility, Cancer Research Technology Program, Frederick National Laboratory, Bethesda, MD 20892, USA., Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: sar@nih.gov.,

Abstract:

Circulating T cells from peripheral blood (PBL) can provide a rich and noninvasive source for antitumor T cells. By single-cell transcriptomic profiling of 36 neoantigen-specific T cell clones from 6 metastatic cancer patients, we report the transcriptional and cell surface signatures of antitumor PBL-derived CD8+ T cells (NeoTCRPBL). Comparison of tumor-infiltrating lymphocyte (TIL)- and PBL-neoantigen-specific T cells revealed that NeoTCRPBL T cells are low in frequency and display less-dysfunctional memory phenotypes relative to their TIL counterparts. Analysis of 100 antitumor TCR clonotypes indicates that most NeoTCRPBL populations target the same neoantigens as TILs. However, NeoTCRPBL TCR repertoire is only partially shared with TIL. Prediction and testing of NeoTCRPBL signature-derived TCRs from PBL of 6 prospective patients demonstrate high enrichment of clonotypes targeting tumor mutations, a viral oncogene, and patient-derived tumor. Thus, the NeoTCRPBL signature provides an alternative source for identifying antitumor T cells from PBL of cancer patients, enabling immune monitoring and immunotherapies. Copyright © 2023. Published by Elsevier Inc.

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